The beneficial health effects of tea (Camellia sinensis) and its major polyphenolic constituent, (-)- epigallocatechin-3-gallate (EGCG), have been extensively studied and publicized. Recently, green tea polyphenols have been used as dietary supplements for weight reduction, however, the efficacy of such preparations remains debatable. Of concern, emerging case reports associate liver toxicity with consumption of green tea-based supplements. Our preliminary studies have indicated that whereas high doses of EGCG are hepatotoxic, moderate doses protect against development of obesity and metabolic syndrome in high-fat fed mice. More importantly, dietary EGCG also prevented the development of obesity-related fatty liver disease (ORFLD). ORFLD is emerging as a serious health problem and represents a significant risk factor for the development of cirrhosis. We hypothesize that dietary administration of EGCG can prevent and reverse the development of ORFLD, but high doses of EGCG are hepatotoxic and the toxicity is potentiated by ORFLD. The protective effects are mediated by the ability EGCG to alter fat absorption and hepatic fat metabolism. The toxic effects arise from the pro-oxidative activity of high dose EGCG. We propose to test these hypotheses as follows: 1. To determine the preventive effects of low dose chronic EGCG against the development of ORFLD in both dietary and genetic mouse models. 2. To determine the mechanisms by which EGCG prevents the development of ORFLD in dietary and genetic mouse models. 3. To characterize the hepatotoxic effects of high doses of EGCG and determine whether this toxicity is potentiated by ORFLD in mice. Successful completion of this grant application will enhance our understanding of the efficacy of green tea polyphenols as ORFLD preventive agents and the mechanisms involved. Further, the dose-response of beneficial versus potential toxic effects of EGCG to the liver will be established, allowing rational design of future pre-clinical and clinical trials. Given the growing obesity epidemic and the increased use of green tea-based dietary supplements for weight loss, the present studies are expected to have significant public health impact. PUBLIC HEALTH RELEVANCE: The rate of obesity and the related complication of fatty liver disease are increasing at a rapid pace; dietary interventions, such as green tea polyphenols, could have significant public health impact. However, the increased use of green tea-based dietary supplements, in which tea extracts are concentrated and/or purified represents a situation in which unforeseen adverse effects could, and have, occurred due to alterations in dose, dosage form, and pharmacokinetics. In this study, we will study the efficacy and mechanisms of action of epigallocatechin-3-gallate (EGCG), the major tea polyphenol, as fatty liver disease preventive agents, as well as the hepatotoxicity of high doses of EGCG. Successful completion of this research will provide important insight into the fatty liver preventive effects of EGCG, establish an upper safety limit for EGCG dose, and identify potential medical situations (i.e. preexisting fatty liver disease) in which individuals may be sensitized to the hepatotoxic effects of EGCG.